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Published on: June 8, 2018
Do DNA Double-Strand Breaks Drive Aging?
1Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave., Bronx, NY 10461, USA.
Abstract:
DNA double-strand breaks (DSBs) are rare, but highly toxic, lesions requiring orchestrated and conserved machinery to prevent adverse consequences, such as cell death and cancer-causing genome structural mutations. DSBs trigger the DNA damage response (DDR) that directs a cell to repair the break, undergo apoptosis, or become senescent. There is increasing evidence that the various endpoints of DSB processing by different cells and tissues are part of the aging phenotype, with each stage of the DDR associated with specific aging pathologies. In this Perspective, we discuss the possibility that DSBs are major drivers of intrinsic aging, highlighting the dynamics of spontaneous DSBs in relation to aging, the distinct age-related pathologies induced by DSBs, and the segmental progeroid phenotypes in humans and mice with genetic defects in DSB repair. A model is presented as to how DSBs could drive some of the basic mechanisms underlying age-related functional decline and death.
Insights
DNA double-strand breaks (DSBs) are toxic DNA lesions. This perspective proposes that DSBs are key drivers of intrinsic aging, linking their repair dynamics to age-related decline and pathologies.
Area of Science:
- Genetics
- Cell Biology
- Gerontology
Background:
- DNA double-strand breaks (DSBs) are critical DNA lesions.
- The DNA damage response (DDR) orchestrates cellular outcomes like repair, apoptosis, or senescence.
- DSB processing is increasingly linked to aging phenotypes and pathologies.
Purpose of the Study:
- To explore the hypothesis that DSBs are major drivers of intrinsic aging.
- To examine the relationship between spontaneous DSB dynamics and aging.
- To discuss age-related pathologies induced by DSBs and progeroid phenotypes.
Main Methods:
- Literature review and synthesis of existing evidence.
- Analysis of spontaneous DSB dynamics in relation to aging.
- Examination of genetic defects in DSB repair and associated phenotypes.
Main Results:
- DSBs are highly toxic and require specific repair machinery.
- Different stages of the DDR are associated with distinct aging pathologies.
- Genetic defects in DSB repair lead to segmental progeroid phenotypes.
Conclusions:
- DSBs are proposed as significant drivers of intrinsic aging.
- A model suggests how DSBs contribute to age-related functional decline and death.
- Understanding DSB dynamics is crucial for aging research.
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